Indian Patents. 213512:A PHARMACEUTICAL COMPOSITION COMPRISING AS ACTIVE INGREDIENT a CRYSTALLINE FORM OF THE COMPOUND OF FORMULA ( I )

Title of Invention	A PHARMACEUTICAL COMPOSITION COMPRISING AS ACTIVE INGREDIENT a CRYSTALLINE FORM OF THE COMPOUND OF FORMULA ( I )
Abstract	The invention concerns α crystalline form of the compound of formula (I), characterised by its X-ray diffraction pattern on powder. The invention is useful for preparing medicines.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "A PHARMACEUTICAL COMPOSITION COMPRISING AS ACTIVE INGREDIENT a CRYSTALLINE FORM OF THE COMPOUND OF FORMULA (I)" LES LABORATOIRES SERVIER, of 12, Place de la Defense, F-92415 Courbevoie Cedexa, France, The following specification particularly describes the invention and the manner in which it is to be performed: The present invention relates to a new a crystalline form of perindopril tert-butylamine salt of formula (I): C02Et tBuNH2 (I), to a process for its preparation and to pharmaceutical compositions containing it. Perindopril and its pharmaceutically acceptable salts, and more especially its tert-butylamine salt, have valuable pharmacological properties. Their principal property is that of rnhibiting angiotensin I converting enzyme (or kininase II), which prevents, on the one hand, conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, degradation of bradykinin (a vasodilator) to an inactive peptide. Those two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, more especially in arterial hypertension and heart failure. Perindopril, its preparation and its use in therapeutics have been described in European Patent specification EP 0 049 658. In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level. The patent specification EP 0 308 341 describes an industrial synthesis process for perindopril. However, that document does not specify the conditions for obtaining perindopril in a form that exhibits those characteristics in a reproducible manner. The Applicant has now found that a particular salt of perindopril, the tert-butylamine salt, can be obtained in a well defined, perfectly reproducible crystalline form that especially exhibits valuable characteristics of filtration, drying and ease of formulation. More specifically, the present invention relates to the a crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg"s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray): Angle 2 theta (o) Inter-planar distance d (A) Intensity Relative intensity (%) 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 21.832 4.07 217 4.9 22.158 4.01 483 11 22.588 3.93 386 8.8 23.323 3.81 107 2.4 24.200 3.67 448. 10.2 24.727 3.60 137 3.1 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28.966 3.08 129 2.9 29.213 3.05 117 2.7 The invention relates also to a process for the preparation of the a crystalline form of the compound of formula (I), which process is characterised in that a solution of perindopril tert-butylamine salt in ethyl acetate is heated at reflux and is cooled gradually until crystallisation is complete. 5 • In the crystallisation process according to the invention it is possible to use the compound of formula (I) obtained by any process. Advantageously, the compound of formula (I) obtained by the preparation process described in patent specification EP 0 308 341 is used. • The concentration of the compound of formula (I) in the ethyl acetate is preferably 10 from 70 to 90 g/litre. • Advantageously, the solution of the compound of formula (I) in ethyl acetate at reflux is first cooled to a temperature of from 55 to 65°C at a rate of from 5 to 10°C/hour, preferably from 6 to 8°C/hour, and then to ambient temperature. • The solution can advantageously be seeded during the cooling step at a temperature of 15 from 76 to 65°C. The perindopril tert-butylamine salt that is thereby obtained is in the form of individual needles about 0.2 mm long. That homogeneous distribution has the advantage of allowing especially rapid and efficient filtration and drying, as well as allowing the preparation of pharmaceutical formulations having a uniform and reproducible composition, which is especially advantageous when those formulations are intended for oral administration. The form thereby obtained is sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level. The invention relates also to pharmaceutical compositions comprising as active ingredient the a crystalline form of the compound of formula (I) together with one or more 5 appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.. 10 The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. It varies from 1 to 500 mg per day in one or more administrations. The pharmaceutical compositions according to the invention may also comprise a diuretic such as indapamide. 15 The following Examples illustrate the invention but do not limit it in any way. The powder X-ray diffraction spectrum was measured under the following experimental conditions : - Siemens D5005 diffractometer, scintillation detector, - copper anticathode ( =1.5405 A), voltage 40 kV, intensity 40 mA, 20 - mounting 6-8, - measurement range : 5° to 30°, - increment between each measurement: 0.02°, - measurement time per step : 2 s, variable slits : v6, 25 - filter Kβ(Nl), - no internal reference, - zeroing procedure using the Siemens slits, experimental data processed using EVA software (version 5.0), EXAMPLE 1 : α crystalline form of perindopril tert-butylamine salt 125 g of perindopril tert-butylamine salt obtained according to the process described in 5 patent specification EP 0 308 341 are dissolved in 1.68 litres of ethyl acetate heated at reflux. T(he temperature of the solution is then brought to 60°C in the course of 2 hours 30 minutes and is then cooled to ambient temperature. The solid obtained is collected by filtration. 10 Powder X-ray diffraction diagram : The powder X-ray diffraction profile (diffraction angles) of the a form of perindopril tert-butylamine salt is given by the significant rays collated in the following table together with the intensity and relative intensity (expressed as a percentage of the most intense ray). Angle 2 theta (o) Inter-planar distance d (A) Intensity Relative intensity (%) 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 226 5.1 -21.832 4.07 217 4.9 22.588 3.93 386 8.8 23.323 3.81 107 2.4 24.200 3.67 448 10.2 24.727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.5 28.966 3.08 129 2.9 29.213 3.05 117 2.7 EXAMPLE 2 : Pharmaceutical composition Preparation formula for 1000 tablets each containing 4 mg of active ingredient : Compound of Example 1 4 g Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc 3 g WE CLAIM 1. Pharmaceutical composition comprising as active ingredient a crystalline form of the compound of formula (I): characterized by the following powder X-ray diffraction diagram, measured using a diffractometer (copper anti-cathode) and expressed in terms of inter-planar distances d, Bregg"s angle 2 theta, Intensity and relative intensity (expressed as a percentage with respect to the most intense ray): Angle 2 theta (o) Inter-planar distance d (A) Intensity Relative intensity (%) 7.680 11.50 390 8.8 8.144 10.85 230 5.2 9.037 9.78 4410 100 10.947 8.08 182 4.1 13.150 6.73 82 1.9 13.687 6.46 83 1.9 14.627 6.05 582 13.2 15.412 5.74 770 17.5 16.573 5.34 1115 25.3 17.357 5.10 340 7.7 18.109 4.89 193 4.4 19.922 4.45 306 6.9 20.609 4.31 375 8.5 21.412 4.15 225 5.1 21.832 4.07 217 4.9 22.158 4.01 483 11 22.588 3.93 386 8.8 23.323 3.81 107 2.4 24.200 3.67 44B 10.2 24.727 3.60 137 3.1 25.957 3.43 125 2.8 26.932 3.31 75 1.7 27.836 3.20 197 4.6 28.966 3.08 129 2.9 29.213 3.05 117 2.7 in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 2. Pharmaceutical composition as claimed in claim 1, wherein it also comprises a diuretic. 3. Pharmaceutical composition as claimed in claim 2, wherein the diuretic is indapamide. Dated this 4th day of November, 2004

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"A PHARMACEUTICAL COMPOSITION COMPRISING AS ACTIVE INGREDIENT a CRYSTALLINE FORM OF THE COMPOUND OF FORMULA (I)"
LES LABORATOIRES SERVIER, of 12, Place de la Defense, F-92415 Courbevoie Cedexa, France,
The following specification particularly describes the invention and the manner in which it is to be performed:

The present invention relates to a new a crystalline form of perindopril tert-butylamine salt of formula (I):

C02Et

tBuNH2 (I),

to a process for its preparation and to pharmaceutical compositions containing it.
Perindopril and its pharmaceutically acceptable salts, and more especially its tert-butylamine salt, have valuable pharmacological properties.
Their principal property is that of rnhibiting angiotensin I converting enzyme (or kininase II), which prevents, on the one hand, conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, degradation of bradykinin (a vasodilator) to an inactive peptide.
Those two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, more especially in arterial hypertension and heart failure.
Perindopril, its preparation and its use in therapeutics have been described in European Patent specification EP 0 049 658.
In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.

The patent specification EP 0 308 341 describes an industrial synthesis process for perindopril. However, that document does not specify the conditions for obtaining perindopril in a form that exhibits those characteristics in a reproducible manner.
The Applicant has now found that a particular salt of perindopril, the tert-butylamine salt, can be obtained in a well defined, perfectly reproducible crystalline form that especially exhibits valuable characteristics of filtration, drying and ease of formulation.
More specifically, the present invention relates to the a crystalline form of the compound of formula (I), characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg"s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray):

Angle 2 theta
(o) Inter-planar distance d (A) Intensity Relative intensity
(%)
7.680 11.50 390 8.8
8.144 10.85 230 5.2
9.037 9.78 4410 100
10.947 8.08 182 4.1
13.150 6.73 82 1.9
13.687 6.46 83 1.9
14.627 6.05 582 13.2
15.412 5.74 770 17.5
16.573 5.34 1115 25.3
17.357 5.10 340 7.7
18.109 4.89 193 4.4
19.922 4.45 306 6.9
20.609 4.31 375 8.5
21.412 4.15 226 5.1
21.832 4.07 217 4.9
22.158 4.01 483 11
22.588 3.93 386 8.8
23.323 3.81 107 2.4
24.200 3.67 448. 10.2
24.727 3.60 137 3.1

26.932 3.31 75 1.7
27.836 3.20 197 4.5
28.966 3.08 129 2.9
29.213 3.05 117 2.7
The invention relates also to a process for the preparation of the a crystalline form of the compound of formula (I), which process is characterised in that a solution of perindopril tert-butylamine salt in ethyl acetate is heated at reflux and is cooled gradually until crystallisation is complete.
5 • In the crystallisation process according to the invention it is possible to use the
compound of formula (I) obtained by any process. Advantageously, the compound of formula (I) obtained by the preparation process described in patent specification EP 0 308 341 is used.
• The concentration of the compound of formula (I) in the ethyl acetate is preferably
10 from 70 to 90 g/litre.
• Advantageously, the solution of the compound of formula (I) in ethyl acetate at reflux
is first cooled to a temperature of from 55 to 65°C at a rate of from 5 to 10°C/hour,
preferably from 6 to 8°C/hour, and then to ambient temperature.
• The solution can advantageously be seeded during the cooling step at a temperature of
15 from 76 to 65°C.
The perindopril tert-butylamine salt that is thereby obtained is in the form of individual needles about 0.2 mm long. That homogeneous distribution has the advantage of allowing especially rapid and efficient filtration and drying, as well as allowing the preparation of pharmaceutical formulations having a uniform and reproducible composition, which is especially advantageous when those formulations are intended for oral administration.

The form thereby obtained is sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.
The invention relates also to pharmaceutical compositions comprising as active ingredient the a crystalline form of the compound of formula (I) together with one or more 5 appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc..
10 The useful dosage can be varied according to the nature and severity of the disorder, the
administration route and the age and weight of the patient. It varies from 1 to 500 mg per day in one or more administrations.
The pharmaceutical compositions according to the invention may also comprise a diuretic such as indapamide.
15 The following Examples illustrate the invention but do not limit it in any way.
The powder X-ray diffraction spectrum was measured under the following experimental conditions :
- Siemens D5005 diffractometer, scintillation detector,
- copper anticathode ( =1.5405 A), voltage 40 kV, intensity 40 mA,
20 - mounting 6-8,
- measurement range : 5° to 30°,
- increment between each measurement: 0.02°,
- measurement time per step : 2 s,
variable slits : v6,
25 - filter Kβ(Nl),
- no internal reference,

- zeroing procedure using the Siemens slits,
experimental data processed using EVA software (version 5.0),
EXAMPLE 1 : α crystalline form of perindopril tert-butylamine salt
125 g of perindopril tert-butylamine salt obtained according to the process described in
5 patent specification EP 0 308 341 are dissolved in 1.68 litres of ethyl acetate heated at
reflux.
T(he temperature of the solution is then brought to 60°C in the course of 2 hours 30 minutes and is then cooled to ambient temperature. The solid obtained is collected by filtration.
10 Powder X-ray diffraction diagram :
The powder X-ray diffraction profile (diffraction angles) of the a form of perindopril tert-butylamine salt is given by the significant rays collated in the following table together with the intensity and relative intensity (expressed as a percentage of the most intense ray).

Angle 2 theta
(o) Inter-planar distance d (A) Intensity Relative intensity
(%)
7.680 11.50 390 8.8
8.144 10.85 230 5.2
9.037 9.78 4410 100
10.947 8.08 182 4.1
13.150 6.73 82 1.9
13.687 6.46 83 1.9
14.627 6.05 582 13.2
15.412 5.74 770 17.5
16.573 5.34 1115 25.3
17.357 5.10 340 7.7
18.109 4.89 193 4.4
19.922 4.45 306 6.9
20.609 4.31 375 8.5
21.412 4.15 226 5.1
-21.832 4.07 217 4.9

22.588 3.93 386 8.8
23.323 3.81 107 2.4
24.200 3.67 448 10.2
24.727 3.60 137 3.1
25.957 3.43 125 2.8
26.932 3.31 75 1.7
27.836 3.20 197 4.5
28.966 3.08 129 2.9
29.213 3.05 117 2.7
EXAMPLE 2 : Pharmaceutical composition
Preparation formula for 1000 tablets each containing 4 mg of active ingredient :
Compound of Example 1 4 g
Hydroxypropylcellulose 2 g
Wheat starch 10 g
Lactose 100 g
Magnesium stearate 3 g
Talc 3 g

WE CLAIM
1. Pharmaceutical composition comprising as active ingredient a crystalline form of the compound of formula (I):

characterized by the following powder X-ray diffraction diagram, measured using a diffractometer (copper anti-cathode) and expressed in terms of inter-planar distances d, Bregg"s angle 2 theta, Intensity and relative intensity (expressed as a percentage with respect to the most intense ray):

Angle 2 theta (o) Inter-planar distance d (A) Intensity Relative intensity (%)
7.680 11.50 390 8.8
8.144 10.85 230 5.2
9.037 9.78 4410 100
10.947 8.08 182 4.1
13.150 6.73 82 1.9
13.687 6.46 83 1.9
14.627 6.05 582 13.2
15.412 5.74 770 17.5
16.573 5.34 1115 25.3
17.357 5.10 340 7.7
18.109 4.89 193 4.4
19.922 4.45 306 6.9
20.609 4.31 375 8.5

21.412 4.15 225 5.1
21.832 4.07 217 4.9
22.158 4.01 483 11
22.588 3.93 386 8.8
23.323 3.81 107 2.4
24.200 3.67 44B 10.2
24.727 3.60 137 3.1
25.957 3.43 125 2.8
26.932 3.31 75 1.7
27.836 3.20 197 4.6
28.966 3.08 129 2.9
29.213 3.05 117 2.7

in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.

2. Pharmaceutical composition as claimed in claim 1, wherein it also comprises a diuretic.
3. Pharmaceutical composition as claimed in claim 2, wherein the diuretic is indapamide.
Dated this 4th day of November, 2004

Documents:

00628-mumnp-2004-affidavit(03-12-2007).pdf

00628-mumnp-2004-cancelled page(15-11-2007).pdf

00628-mumnp-2004-claims(granted)-(01-08-2007).pdf

00628-mumnp-2004-claims(granted)-(04-11-2004).doc

00628-mumnp-2004-correspondence(23-11-2007).pdf

00628-mumnp-2004-correspondence(ipo)-(15-10-2007).pdf

00628-mumnp-2004-drawing(15-09-2007).pdf

00628-mumnp-2004-form 1(01-08-2007).pdf

00628-mumnp-2004-form 1(04-11-2004).pdf

00628-mumnp-2004-form 13(06-08-2007).pdf

00628-mumnp-2004-form 19(14-12-2004).pdf

00628-mumnp-2004-form 2(granted)-(01-08-2007).pdf

00628-mumnp-2004-form 2(granted)-(04-11-2004).doc

00628-mumnp-2004-form 3(02-11-2004).pdf

00628-mumnp-2004-form 3(10-12-2004).pdf

00628-mumnp-2004-form 5(02-11-2004).pdf

00628-mumnp-2004-power of authority(01-08-2007).pdf

00628-mumnp-2004-power of authority(02-11-2004).pdf

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Patent Number

213512

Indian Patent Application Number

628/MUMNP/2004

PG Journal Number

09/2008

Publication Date

29-Feb-2008

Grant Date

07-Jan-2008

Date of Filing

04-Nov-2004

Name of Patentee

LES LABORATOIRES SERVIER

Applicant Address

12, PLACE DE LA DEFENSE, F-92415 COURBEVOIE CEDEX.

Inventors:

#	Inventor's Name	Inventor's Address
1	BRUNO PFEIFFER	47, RUE ERNEST RENAN, 95320 SAINT LEU LA FORET.
2	YVES-MICHEL GINOT	8, QUAI SAINT LAURENT, 45000 ORLEANS.
3	GERARD COQUEREL	192, RUE DE 1'EGLISE, 76520 BOOS.
4	STEPHANE BEILLES	35, PLACE DE LA BASSE VIEILLE TOUR, 76000 ROUEN.

PCT International Classification Number

C07D209/42 A61K31/47

PCT International Application Number

PCT/FR01/02167

PCT International Filing date

2001-07-06

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	00/08793	2000-07-06	France